SYSTEMATIC REVIEW
published: 25 June 2021
Edited by:
Lin Yang,
Hong Kong Polytechnic University,
Hong Kong, SAR China
Reviewed by:
Matthias Walter,
University Hospital Basel, Switzerland
Jinjun Ran,
Shanghai Jiao Tong University, China
*Correspondence:
Bahareh Hajikhani
Hajikhani@sbmu.ac.ir
Specialty section:
This article was submitted to
Infectious Diseases - Surveillance,
Prevention and Treatment,
a section of the journal
Frontiers in Medicine
Received: 16 March 2021
Accepted: 02 June 2021
Published: 25 June 2021
Citation:
Dadashi M, Khaleghnejad S, Abedi
Elkhichi P, Goudarzi M, Goudarzi H,
Taghavi A, Vaezjalali M and
Hajikhani B (2021) COVID-19 and
Influenza Co-infection: A Systematic
Review and Meta-Analysis.
Front. Med. 8:681469.
doi: 10.3389/fmed.2021.681469
Frontiers in Medicine | www.frontiersin.org
doi: 10.3389/fmed.2021.681469
COVID-19 and Influenza Co-infection:
A Systematic Review and
Meta-Analysis
Masoud Dadashi 1,2 , Saeedeh Khaleghnejad 3 , Parisa Abedi Elkhichi 3,4 , Mehdi Goudarzi 3 ,
Hossein Goudarzi 3 , Afsoon Taghavi 5 , Maryam Vaezjalali 3 and Bahareh Hajikhani 3*
1
Department of Microbiology, School of Medicine, Alborz University of Medical Sciences, Karaj, Iran, 2 Non Communicable
Diseases Research Center, Alborz University of Medical Sciences, Karaj, Iran, 3 Department of Microbiology, School of
Medicine, Shahid Beheshti University of Medical Sciences, Tehran, Iran, 4 Medical Microbiology Research Center, Qazvin
University of Medical Sciences, Qazvin, Iran, 5 Department of Pathology, School of Medicine, Shahid Beheshti University of
Medical Sciences, Tehran, Iran
Background and Aim: Co-infection of COVID-19 with other respiratory pathogens
which may complicate the diagnosis, treatment, and prognosis of COVID-19 emerge
new concern. The overlap of COVID-19 and influenza, as two epidemics at the same
time can occur in the cold months of the year. The aim of current study was to evaluate
the rate of such co-infection as a systematic review and meta-analysis.
Methods: A systematic literature search was performed on September 28, 2019 for
original research articles published in Medline, Web of Science, and Embase databases
from December 2019 to September 2020 using relevant keywords. Patients of all
ages with simultaneous COVID-19 and influenza were included. Statistical analysis was
performed using STATA 14 software.
Results: Eleven prevalence studies with total of 3,070 patients with COVID-19, and
79 patients with concurrent COVID-19 and influenza were selected for final evaluation.
The prevalence of influenza infection was 0.8% in patients with confirmed COVID-19.
The frequency of influenza virus co-infection among patients with COVID-19 was 4.5%
in Asia and 0.4% in the America. Four prevalence studies reported the sex of patients,
which were 30 men and 31 women. Prevalence of co-infection with influenza in men and
women with COVID-19 was 5.3 and 9.1%, respectively. Eight case reports and 7 case
series with a total of 123 patients with COVID-19 were selected, 29 of them (16 men, 13
women) with mean age of 48 years had concurrent infection with influenza viruses A/B.
Fever, cough, and shortness of breath were the most common clinical manifestations.
Two of 29 patients died (6.9%), and 17 out of 29 patients recovered (58.6%). Oseltamivir
and hydroxychloroquine were the most widely used drugs used for 41.4, and 31% of
patients, respectively.
Conclusion: Although a low proportion of COVID-19 patients have influenza
co-infection, however, the importance of such co-infection, especially in high-risk
1 June 2021 | Volume 8 | Article 681469
Dadashi et al.
individuals and the elderly, cannot be ignored. We were unable to report the exact rate
of simultaneous influenza in COVID-19 patients worldwide due to a lack of data from
several countries. Obviously, more studies are needed to evaluate the exact effect of the
COVID-19 and influenza co-infection in clinical outcomes.
Keywords: coronavirus, COVID-19, influenza virus, co-infection, meta-analysis, systematic review
INTRODUCTION
The severe acute respiratory syndrome coronavirus 2 (SARS-
CoV-2) causes a rapid spreading viral pneumonia; known as
coronavirus disease 2019 (COVID-19) originated from China
in December 2019, and now become a worldwide public health
emergency and finally becomes a global pandemic (1).
Recognition of COVID-19 is critical as it allows effective
infection control measures and potentially beneficial antiviral
therapy to be introduced, but the risk of COVID-19 co-infection
should not be ignored.
COVID-19 co-infections with other respiratory pathogens
which may complicate the diagnosis, treatment, prognosis of
COVID-19 emerge new concern. These co-infections may even
increase the disease symptom and mortality rate (2). The damage
of respiratory ciliated cells due to some viral infections can also
facilitate the conditions for an infection with SARS-CoV-2. The
overlap of COVID-19 and influenza, as two epidemics at the
same time can occur in the cold months of the year as seasonal
influenza period begin. Both influenza virus A/B and SARS-
CoV-2 are transmitted via close contact, respiratory droplets and
contaminated surfaces, and cause a wide range of asymptomatic
or mild to severe disease such as flu-like symptoms, pneumonia,
loose of taste and smell, and even death (3–5).
There have been several studies published from different parts
of world about COVID-19 co-infection with other pathogens
especially influenza virus A/B. However, a systematic review
that summarizes the results of existing studies has not yet
been conducted.
Due to the importance of this issue, the aim of the present
study was to systematically review the literature on COVID-19
co-infections with the influenza virus (type A and/or B) and
potentially conduct a meta-analysis if possible.
METHODS
The present systematic review and meta-analysis was conducted
according to the “Preferred Reporting Items for Systematic
Reviews and Meta-Analyses” (PRISMA) (6).
Search Strategy and Study Selection
The three most important electronic databases included
PubMed, Web of Science, and Embase were searched on
September 28, 2019 to identify studies published in English
from December 2019 to September 2020 as follows: (“COVID-
19”[Title/Abstract] OR “novel coronavirus 2019”[Title/Abstract]
OR “2019 ncov”[Title/Abstract] OR “nCoV”[Title/Abstract]
OR “severe acute respiratory syndrome coronavirus
2”[Title/Abstract] OR “SARSCoV-2”[Title/Abstract]) AND
Frontiers in Medicine | www.frontiersin.org
COVID-19 and Influenza Co-Infection
(“influenza”[Title/Abstract] OR “orthomyxoviridae”[MeSH
Terms] OR “influenza virus”[Title/Abstract] OR
“flu”[Title/Abstract] OR “flu”[Title/Abstract]).
In addition, the reference lists of covered studies were also
checked to avoid missing suitable publications. Two different
investigators independently checked this process (MG, AT).
PICO algorithm was adopted to define inclusion and exclusion
criteria for study selection. Accordingly, we evaluated the data
on P (Patient, Population or Problem) = patients with COVID-
19, I (Intervention or exposure) = influenza virus infection, C
(Comparison) = not available, and O (Outcome) = co-infection
COVID-19 and influenza A/B.
All clinical studies investigating the presence of influenza
virus infection in patients with COVID-19 were selected, except
articles that reported only the prevalence of COVID-19 or the
prevalence of influenza alone, review articles, abstracts presented
in conferences, and duplicate studies. Relevant prevalence
studies, case reports and case series were included. In the next
step, titles and abstracts of all selected papers were screened by
two investigators (SKN, PA).
Data Extraction
First author name; year of publication; type of study, country
where the study was conducted; age and gender of patients,
number of patients with confirmed COVID−19, number of
patients with influenza co-infection and type of influenza
virus were extracted from all eligible articles, and transfer
to a data extraction form. To avoid any bias, two authors
independently recorded the data (SKN, PA). The discrepancy
was resolved by discussing between authors (BH, MD,
and MG).
Quality Assessment
Quality assessment of included publications was performed
using a checklist provided by the Joanna Briggs Institute (JBI)
which assist in assessing the trustworthiness, relevance and
results of published papers (7). Two investigators (HG, MV)
checked the quality of included studies andthe publication
bias independently.
Statistical Analysis
Statistical analyses were performed with STATA (version 14,
IC; Stata Corporation, College Station, TX, USA). Meta-analysis
of the continent-, country-, age-, sex-, and influenza virus
type- specific prevalence rates of co-infection observed in the
considered studies were conducted. We estimated the pooled
proportion of co-infected patients. The pooled frequency with
95% confidence intervals (CI) was assessed using the fixed-effects
(FEM), and the random effects models (REM). We assessed
2 June 2021 | Volume 8 | Article 681469
Dadashi et al.
statistical heterogeneity using the I2 statistical method. Cochran’s
Q and the I2 statistic were used to determine between-study
heterogeneity. Begg’s and Egger’s tests were used to measure
publication bias statistically (p < 0.05 was considered statistically
relevant publication bias).
RESULTS
Our initial search retrieved 2,412 articles, after removing
duplicates, 1,530 articles remain for the secondary screening.
Following title and abstract screening 1,250 of the chosen
articles were excluded. Guidelines, review articles, duplicate
articles, systematic reviews, unrelated articles, and articles
in languages other than English were among the excluded
articles. After reviewing the full text of 280 studies, eventually,
FIGURE 1 | Flow chart of study selection for inclusion in the systematic review and meta-analysis.
Frontiers in Medicine | www.frontiersin.org
COVID-19 and Influenza Co-Infection
26 studies met the inclusion criteria and were included
for the final analysis (Figure 1). Final selected articles
encompass 11 prevalence studies, 15 case report/case
series. Tables 1, 2 summarized the characteristics of the
included articles.
Prevalence Studies
Eleven prevalence studies were evaluated in the present review
[4 reported from China (36.3%), 3 from USA (27.3%), and
Brazil, Switzerland, Italy, and Iran each reported 1 study
(9.1%)]. These studies had 3,070 participants with COVID-19 of
which 79 patients had influenza co-infection. Sixty seven and 9
patients had an influenza co-infection A or B, respectively. The
pooled prevalence of Influenza co-infection among patients with
COVID-19 was 0.8 % (95% CI: 0.4–1.3).
3 June 2021 | Volume 8 | Article 681469
Dadashi et al. COVID-19 and Influenza Co-Infection

TABLE 1 | Characteristics of included prevalence studies.

First author Published time Country Patients with Patients with IV-A IV-B Co-infected patients
COVID-19 COVID-19–Influenza
co-infection (%) Mean age Male/Female

Castillo et al. (8) July, 2020 USA 42 1 (2.4) 1 0 21 1/0

Ding et al. (9) March, 2020 China 115 5 (4.3) 3 2 50.2 2/3
Garazzino et al. (10) May, 2020 Italy 168 1 (0.6) 1 nr nr Nr
Hashemi1 et al. (11) July, 2020 Iran 105 23 (21.9) 23 0 nr 14/9
Hu et al. (12) March, 2020 China 70 32 (45.7) 32 0 62.8 13/19
Kim et al. (13) April, 2020 USA 116 1 (0.9) 1 0 74 Nr
Leuzinger et al. (14) July, 2020 Switzerland 930 2 (0.2) 2 0 >16 Nr
de Suoza Luca et al. (15) May, 2020 Brazil 115 1 (0.9) 0 1 36 Nr
Ma et al. (16) Jun, 2020 China 250 3 (1.2) 2 1 nr Nr
Takahashi et al. (17) Sep, 2020 USA 902 3 (0.3) nr Nr nr Nr
Zhu et al. (18) May, 2020 China 257 7 (2.7) 2 5 15–44 Nr

All studies used real time-polymerase chain reaction (RT-PCR) as their detection method except Hu study which used Elisa method, Ding et al., and Hashemi et al. which did not provided
information of their detection method. nr, not reported; IV-A, Influenza Virus A; IV-B, Influenza Virus B.

TABLE 2 | Characteristics of included case report/case series.

First author Type of study Published time Country Patients with Patients with IV-A IV-B Co-infected patients
COVID-19 COVID-19 Influenza
co-infection Mean age Male/Female

Azekawa et al. (19) Case report April, 2020 Japan 1 1 1 0 78 0/1

Benkovic et al. (20) Case report Oct, 2020 USA 4 1 1 0 65 1/0
Cuadrado-Payán et al. (21) Case series May, 2020 Spain 4 4 3 2 67 3/1
Danis et al. (22) Case series Apr, 2020 France 13 1 1 0 9 1/0
Huang et al. (23) Case report Jun, 2020 China 1 1 0 1 48 0/1
Kakuya et al. (24) Case report May, 2020 Japan 3 1 1 0 11 1/0
Khodamoradi et al. (25) Case series April, 2020 Iran 4 4 4 0 57 3/1
Konala et al. (26) Case series May, 2020 USA 3 3 3 0 53.3 1/2
Konala et al. (27) Case report April, 2020 USA 1 1 1 0 66 0/1
Li et al. (28) Case report Jun, 2020 China 1 1 1 0 10 1/0
Miatech et al. (29) Case series Oct, 2020 China 81 4 2 2 61.5 2/2
Sang et al. (30) Case report May, 2020 USA 1 1 1 0 58 0/1
Singh et al. (31) Case series Aug, 2020 USA 3 3 1 2 59.6 1/2
Wu et al. (32) Case report June, 2020 China 1 1 1 0 69 1/0
Zou et al. (33) Case series Jun, 2020 China 2 2 2 0 7.7 1/1

All studies used Real time-Polymerase Chain Reaction (RT-PCR) as their detection method. nr, not reported; IV-A, Influenza Virus A; IV-B, Influenza Virus B.

An examination of publication bias was carried out by
visual observation of the funnel plot (Supplementary Figure 1).
Given the small number of studies, the funnel plots revealed
some asymmetry. Then, to provide statistical evidence
of funnel plot asymmetry, Egger’s and Begg’s tests were
used. The results showed no signs of publication bias
(p-values for Egger’s and Begg’s tests were 0.9 and 0.3,
respectively). Forest plot and Galbraith of the meta-analysis
on the prevalence of COVID-19 and Influenza co-infection
among patients with COVID-19 are shown in Figure 2, and
Supplementary Figure 2, respectively.
The meta-analysis of prevalence studies revealed that the
frequency of influenza virus co-infection among patients with
COVID-19 was 4.5% (95% CI 0.1–7.9) in Asia (5 studies, 70
patients), and 0.4 % (95% CI 0.0–0.7) from the American
continent (4 studies, 6 patients). There were no reports of co-
infection with influenza virus A/B in patients with COVID-19
from Africa or Oceania at the time of this study. The prevalence
of co-infection with influenza in men (30 patients in 4 studies)
and women (31 patients in 3 studies) with COVID-19 was
5.3 and 9.1%, respectively. The rate of co-infection in the age
groups of <50 years, and more than 50 years was 1.7 and 4.6%,
respectively. Table 3 shows more details of subgroup analysis of
the studies.
Case Reports/Case Series Studies
Eight case reports (i.e., total 13 patients) and seven case reports
(i.e., total 110 patients) highlighted an influenza co-infection in

Frontiers in Medicine | www.frontiersin.org 4 June 2021 | Volume 8 | Article 681469

 Dadashi et al. COVID-19 and Influenza Co-Infection

FIGURE 2 | Forest plot of the meta-analysis of data from single studies.

TABLE 3 | Frequency of Influenza co-infection among patients with COVID-19 based on different subgroups.

patients with COVID-19 and Prevalence% Number of Number of I-squared

Influenza (95% CI) studies patients

Overall 0.8 (0.4–1.3) 11 79 76.6%

Country Continent

America 0.4 (0.0–0.7) 4 6 43.4%

Asia 4.5 (0.1–7.9) 5 70 84.4%

China 3.1 (0.2–6) 4 47 81.7%

USA 0.7 (0.0–1.4) 3 5 52.6%

Male 5.3 (1.3–9.4) 4 30 80.1%

Virus type Gender

Female 9.1 (0.6–17.2) 3 31 83.5%

Influenza virus A 8 (5.6–10.4) 9 67 62.6%

Influenza virus B 5.5 (2.8–8.3) 4 9 52.9%

<50 years 1.7 (0.4–3) 3 9 51.2%

Age

More than 50 years 4.6 (1.4–10.6) 3 38 87.6%

8 and 21 COVID-19 patients, respectively. Of these 29 patients age of patients was 48 years. Characteristics of these 15 studies
(i.e., 13 women and 16 men), influenza type distribution was which were not taken into account during the meta-analyses are
A = 22 (75.9%), B = 6 (20.7%) or both = 1 (3.4). The mean described in Table 2.

Frontiers in Medicine | www.frontiersin.org 5 June 2021 | Volume 8 | Article 681469

Dadashi et al. COVID-19 and Influenza Co-Infection

TABLE 4 | Comorbidities in coinfected patients in case reports/case series TABLE 6 | Laboratory and imaging findings of co-infected patients in case
studies among a total of 29 evaluated patients. reports/case series studies among a total of 29 evaluated patients.

Variables Number of studies n* (%) Variables Number of studies n* (%)

Atrial fibrillation 1 1 (3.4) Leukopenia 1 1 (3.4)

Hyperlipidemia 1 1 (3.4) Lymphopenia 3 6 (20.7)
Hypertension 7 17 (58.6) Leukocytosis 2 2 (6.9)

Laboratory finding
Diabetes mellitus 7 14 (48.3) Elevated blood urea nitrogen 3 3 (10.3)
Rheumatoid arthritis 1 1 (3.4) Elevated creatinine 3 4 (13.8)
Interstitial lung disease 1 1 (3.4) Elevated interleukin-6 levels 2 6 (20.7)
Chronic obstructive pulmonary disease 1 1 (3.4) Elevated ESR 4 10 (34.5)
Haemodialysis 4 5 (17.2) Elevated creatine kinase 1 3 (10.3)
Hypothyroidism 1 1 (3.4) Elevated Lactate dehydrogenase 3 5 (17.2)
Dyslipidemia 2 2 (6.9) Elevated C-reactive protein 5 16 (55.2)
Myocardial infarction 1 1 (3.4) Elevated D-dimer 3 7 (24.1)

Imaging
Gastroesophageal reflux disease 1 1 (3.4) Chest X-ray: lung infiltrates 10 19 (65.5)
Chronic kidney disease 3 3 (10.3) CT Scan: ground-glass opacities 6 9 (31.0)
Congestive heart failure 1 1 (3.4)
*n, number of co-infected patients with any variables; ESR, erythrocyte sedimentation
Coronary artery disease 1 1 (3.4) rate; CT, computerized tomography.

*n, number of co-infected patients with any variables.

Based on the results of included studies, nasopharyngeal swabs

were the most common method of sampling for molecular
TABLE 5 | Clinical manifestation of co-infected patients in case reports/case
series studies among a total of 29 evaluated patients. evaluations (52%). Throat swab and sputum were only used for
two and one patient, respectively.
Variables Number of studies n* (%) After reviewing the laboratory findings recorded in the
evaluated articles, it was found that the use of nasopharyngeal
Cough 11 23 (79.3)
swabs was the most common method of sampling to diagnose
Fever 14 26 (89.4)
the infection in patients. It was also found that elevated C-
Respiratory distress 1 1 (3.4)
reactive protein (CRP) (55.2%), erythrocyte sedimentation rate
Dyspnoea 3 6 (20.7)
(ESR) (34.5%), and increased D-dimer (24.1%) were the most
Tachypnoea 2 5 (17.2)
commonly reported findings, respectively. Leukopenia (3.4%)
Bronchospasm 1 4 (13.8)
was the least reported abnormality.
Sputum production 2 2 (6.9) The outcomes of COVID-19-Influenza co-infection were
Gastrointestinal symptoms 2 2 (6.9) reported in 11 studies. According to them, 2 of 29 patients died
Malaise 2 2 (6.9) (6.9%), and 17 out of 29 patients recovered (58.6%). Table 6
Headache 2 5 (17.2) provides more information in this regard.
Shortness of breath 4 7 (24.1) In the case reports/case series studies, the drugs used for
Body pain 1 2 (6.9) treatment of patients with COVID-19 co-infected with influenza
Myalgia 5 6 (20.7) virus divided into sections such as antiviral drugs, antibacterial
*n, number of co-infected patients with any variables.
drugs, and a combination of drugs (Table 5). Oseltamivir was
the most widely used antiviral drugs reported in 8 studies.
Hydroxychloroquine was also one of the most widely used drugs,
as reported by 4 studies, 31% of evaluated patients received
As the details of these studies are listed in Table 4, this agent. Among the antibacterial drugs azithromycin and
it can be seen that hypertension (58.6%) and diabetes ceftriaxone were more common antibiotics each was used in 4,
mellitus (48.3%) were among the most prevalent co-morbidities and 3 studies, respectively. Details of the treatment regimens used
of co-infected patients. Haemodialysis with the prevalence in the reviewed studies are presented in Table 7.
of 17.2% was the third most common co-morbidity in
these patients. DISCUSSION
The clinical symptoms were also checked in patients
with COVID-19 and influenza virus co-infection. Fever, COVID-19 as a highly transmissible viral infection which led
cough, and shortness of breath were the most common to thousands of deaths worldwide has challenged the world’s
clinical manifestations reported in this group of patients healthcare systems (34). Therefore, several studies have been
with a frequency of 89.4, 79.3, and 24.1 percent, performed to identify how the infection occurs, its symptoms
respectively (Table 5). and complications, as well as the factors involved in increasing

Frontiers in Medicine | www.frontiersin.org 6 June 2021 | Volume 8 | Article 681469

 Dadashi et al.
TABLE 7 | Agents used in the treatment of patients with COVID-19 and Influenza
co-infection among a total of 29 evaluated patients.
Agent Number of
studies
Peramivir
Antiviral drug
Cefaclor
Oseltamivir
Lopinavir–ritonavir
Lianhua qingwen
Antibacterial Azithromycin
drug Ceftriaxon
Levofloxacin
Other Hydroxychloroquine
Oseltamivir, Levofloxacin
Combination therapy
Oseltamivir, Cefaclor
Oseltamivir, Lianhua qingwen
Oseltamivir, Ceftriaxon, Azithromycin
Oseltamivir, Hydroxychloroquine,
Ceftriaxon, Azithromycin
Hydroxychloroquine,
Lopinavir–ritonavir
*n, number of co-infected patients’ receiving each medication.
its severity and mortality, and it is still the subject of studies. Co-
occurrence of infections can be one of the causes of exacerbation
of this disease. Lansbury et al. in their recent meta-analysis
of 30 studies reports the pooled proportions of bacterial and
viral co-infections in patients with COVID-19 were 7 and 3%,
respectively (35).
In some viral infections, simultaneous infections with other
bacterial and viral agents can exacerbate complications and
increase disease mortality. The same can be said for SARS-
CoV2 infection; however, there is not enough evidence to suggest
that such concurrent infections increase disease morbidity
or mortality.
COVID-19 often presents with nonspecific flu like respiratory
symptoms. Influenza virus infection is thought to be similar
to COVID-19 in clinical presentation, transmission mechanism,
and seasonal coincidence. Simultaneous infection with influenza
and SARS-CoV2 can interfere with the diagnosis and treatment
of patients. In addition, this co-infection, especially in high-
risk groups of patients, may aggravate the symptoms and
complications of the disease (35).
SARS-CoV-2 and influenza virus are both airborne pathogens
that affect the respiratory tract. Furthermore, SARS-CoV-2
appears to preferentially infect alveolar type II cells (AT2
pneumocytes), which are also the primary site of influenza virus
replication. This can exacerbate the side effects of COVID-19
if there is a concomitant flu infection (36, 37). As a result,
the COVID-19 pandemic and seasonal influenza could put a
large population at risk of contracting both viruses at the same
time. To confirm the role of seasonal flu in the severity of the
COVID-19 pandemic, Bai et al. in their research provide the
first experimental evidence and reported that the preinfection
Frontiers in Medicine | www.frontiersin.org
COVID-19 and Influenza Co-Infection
with influenza virus strongly promotes SARS-CoV-2 virus entry
and infectivity in cells and animals. They demonstrated that
n* (%)
among the viruses tested; only IAV enhanced SARS-CoV-2
infection (38). This underscores the importance of the risk
of influenza infection in patients with COVID-19. Especially
1 1 (3.4) in people with underlying factors, the occurrence of such a
1 1 (3.4) concomitant infection can aggravate the complications caused
8 12 (41.4) by COVID-19.
1 4 (13.8) Due to the onset of influenza infection in the cold seasons
1 1 (3.4) of the year, scattered reports have been published about the
4 7 (24.1) influenza co-infection in patients with COVID-19 from the
3 5 (17.2) countries of the Northern Hemisphere that were in the cold
2 3 (10.3) seasons at the time of performing this study. Since there are
4 9 (31.0) no accurate statistics on the rate of such concurrent infections,
1 1 (3.4) herein, we evaluated the results of prevalence studies as well as
case reports and case series in this field in the form of meta-
1 1 (3.4)
1 1 (3.4) analysis and systematic review.
1 1 (3.4) According to a study recently published from China,
2 3 (10.3) concurrent infection of SARS-CoV-2 and influenza virus was
common during the initial COVID-19 outbreak in Wuhan, and
1 4 (13.8) patients who had co-infection encounter a higher risk of poor
health outcomes (39).
Our meta-analysis indicated that overall 1.2% of COVID-19
patients had influenza co-infection. Reports of the frequency
of co-infection between COVID-19 and influenza vary from
different parts of the world. Lansbury et al. estimated that 3% of
patients hospitalized with COVID-19 were also co-infected with
another respiratory virus. Based on their analysis, respiratory
syncytial virus and influenza-A being the most common viral
pathogens in co-infected patients (35).
It should be noted that all studies reviewed in the present
study used the molecular method to confirm the presence of
SARS-CoV-2 as well as influenza viruses, except for one study
in which the presence of infection was diagnosed serologically
through detection of IgM. Since serological test is not highly
specific and may result in overestimation of infections the overall
rate of co-infection reported in that study was higher than
others (12).
Overall, the rate of co-infection with COVID-19 and influenza
has been reported between 0.24 and 44% in the reviewed
studied. This dispersion and difference can be due to the
study population, the underlying conditions of the patients,
the method of confirming the infection as well as the time
and place of the investigation in terms of the prevalence
of influenza.
Influenza co-infection among patients with COVID-19 was
more reported from Asia and China country. Given the high
population of Asia, as well as China, it is reasonable to be likely
that patients with COVID-19, as well as influenza in the region
be more prevalent, other studies have reported similar statistics
too (40, 41).
Based on the results of prevalence studies that reported the
influenza virus type involved in the development of infection in
patients with COVID-19, it was found that the prevalence of type
A virus was higher than type B. This was to be expected due to
the higher overall prevalence of influenza virus type A than type
B (42).
7 June 2021 | Volume 8 | Article 681469
Dadashi et al.
Finally we should mention the limitations of our study. Since
there is not enough information from many countries, we were
not able to fully demonstrate the prevalence of influenza infection
in COVID-19 patients worldwide. Many COVID-19 patients
with influenza may not have been hospitalized and most of them
could have been treated at home. Also, some articles lacked the
necessary information to be added to the present study, and
we had to exclude them. In addition, only studies published in
English were included, which may have caused important studies
to be missed. Finally, the heterogeneity exists among the included
publications. Despite the random effects model allows for the
presence of heterogeneity, there may still be some controversy
about combining study estimates in its presence.
CONCLUSION
Although transmission of other respiratory viruses, including
influenza, has decreased with the implementation of preventive
measures such as social distancing and mask wearing, however,
due to the importance of the issue and the possibility of
severe complications in a group of high-risk or hospitalized
REFERENCES
1. Vermisoglou E, Panacek D, Jayaramulu K, Pykal M, Frebort I, Kolar M, et al.
Human virus detection with graphene-based materials. Bio Bioelectr. (2020)
166:112436. doi: 10.1016/j.bios.2020.112436
2. Zoran MA, Savastru RS, Savastru DM, Tautan MN. Assessing the
relationship between surface levels of PM2.5 and PM10 particulate
matter impact on COVID-19 in Milan, Italy. Sci Total Environ. (2020)
738:139825. doi: 10.1016/j.scitotenv.2020.139825
3. Iqbal MM, Abid I, Hussain S, Shahzad N, Waqas MS, Iqbal MJ. The effects
of regional climatic condition on the spread of COVID-19 at global scale. Sci
Total Environ. (2020) 739:140101. doi: 10.1016/j.scitotenv.2020.140101
4. Bai Y, Yao L, Wei T, Tian F, Jin D-Y, Chen L, et al. Presumed
asymptomatic carrier transmission of COVID-19. JAMA. (2020) 323:1406–
7. doi: 10.1001/jama.2020.2565
5. Sameni F, Hajikhani B, Yaslianifard S, Goudarzi M, Owlia P, Nasiri MJ,
et al. COVID-19 and skin manifestations: an overview of case reports/case
series and meta-analysis of prevalence studies. Front Med. (2020) 7:573188.
doi: 10.3389/fmed.2020.573188
6. Moher D, Liberati A, Tetzlaff J, Altman DG. Preferred reporting items for
systematic reviews and meta-analyses: the PRISMA statement. Ann Intern
Med. (2009) 151:264–9. doi: 10.7326/0003-4819-151-4-200908180-00135
7. Joanna Briggs Institute Reviewers’ Manual: 2017 edition. Adelaide: The Joanna
Briggs Institute (2017).
8. Castillo EM, Coyne CJ, Brennan JJ, Tomaszewski CA. Rates of co-infection
with other respiratory pathogens in patients positive for coronavirus
disease 2019 (COVID-19). J Am Coll Emerg Physic Open. (2020) 1:592–
6. doi: 10.1002/emp2.12172
9. Ding Q, Lu P, Fan Y, Xia Y, Liu M. The clinical characteristics of pneumonia
patients coinfected with 2019 novel coronavirus and influenza virus in
Wuhan, China. J Med Virol. (2020) 92:1549–55. doi: 10.1002/jmv.25781
10. Garazzino S, Montagnani C, Donà D, Meini A, Felici E, Vergine G,
et al. Multicentre Italian study of SARS-CoV-2 infection in children and
adolescents, preliminary data as at 10 April 2020. Eurosurveillance. (2020)
25:2000600. doi: 10.2807/1560-7917.ES.2020.25.18.2000600
11. Hashemi SA, Safamanesh S, Ghasemzadeh-Moghaddam H, Ghafouri M,
Azimian A. High prevalence of SARS-CoV-2 and influenza A virus (H1N1)
coinfection in dead patients in Northeastern Iran. J Med Virol. (2021)
93:1008–12. doi: 10.1002/jmv.26364
Frontiers in Medicine | www.frontiersin.org
COVID-19 and Influenza Co-Infection
patients influenza vaccination, especially in the elderly, is
strongly recommended.
DATA AVAILABILITY STATEMENT
The raw data supporting the conclusions of this article will be
made available by the authors, without undue reservation.
AUTHOR CONTRIBUTIONS
MD and BH designed the study. BH and MG conducted
the search strategy. SK, PA, AT, and MV performed the data
extraction. HG and BH wrote and edited the manuscript. MD
carried out the statistical analysis. All authors contributed to the
article and approved the submitted version.
SUPPLEMENTARY MATERIAL
The Supplementary Material for this article can be found
online at: https://www.frontiersin.org/articles/10.3389/fmed.
2021.681469/full#supplementary-material
12. Hu Z-W, Wang X, Zhao J-P, Ma J, Li H-C, Wang G-F, et al.
Influenza A virus exposure may cause increased symptom severity
and deaths in coronavirus disease 2019. Chin Med J. (2020)
133:2410. doi: 10.1097/CM9.0000000000000966
13. Kim D, Quinn J, Pinsky B, Shah NH, Brown I. Rates of co-infection between
SARS-CoV-2 and other respiratory pathogens. JAMA. (2020) 323:2085–
6. doi: 10.1001/jama.2020.6266
14. Leuzinger K, Roloff T, Gosert R, Sogaard K, Naegele K, Rentsch K, et al.
Epidemiology of severe acute respiratory syndrome coronavirus 2 emergence
amidst community-acquired respiratory viruses. J Infect Dis. (2020) 222:1270–
9. doi: 10.1093/infdis/jiaa464
15. de Souza Luna LK, Perosa DAH, Conte DD, Carvalho JMA, Alves VRG, Cruz
JS, et al. Different patterns of Influenza A and B detected during early stages
of COVID-19 in a university hospital in São Paulo, Brazil. J Infect. (2020)
81:e104–5. doi: 10.1016/j.jinf.2020.05.036
16. Ma L, Wang W, Le Grange JM, Wang X, Du S, Li C, et al. Coinfection
of SARS-CoV-2 and other respiratory pathogens. Infect Drug Resist. (2020)
13:3045–53. doi: 10.2147/IDR.S267238
17. Takahashi M, Egorova NN, Kuno T. COVID-19 and influenza testing in New
York City. J Med Virol. (2020) 93:698–701. doi: 10.1002/jmv.26500
18. Zhu X, Ge Y, Wu T, Zhao K, Chen Y, Wu B, et al. Co-infection
with respiratory pathogens among COVID-2019 cases. Virus Res. (2020)
285:198005. doi: 10.1016/j.virusres.2020.198005
19. Azekawa S, Namkoong H, Mitamura K, Kawaoka Y, Saito F. Co-
infection with SARS-CoV-2 and influenza A virus. IDCases. (2020)
20:e00775. doi: 10.1016/j.idcr.2020.e00775
20. Benkovic S, Kim M, Sin E. Four cases: HIV and SARS-CoV-2 Co-
infection in patients from Long Island, New York. J Med Virol. (2020).
doi: 10.1002/jmv.26029
21. Cuadrado-Payán E, Montagud-Marrahi E, Torres-Elorza M, Bodro M, Blasco
M, Poch E, et al. SARS-CoV-2 and influenza virus co-infection. Lancet. (2020)
395:e84. doi: 10.1016/S0140-6736(20)31052-7
22. Danis K, Epaulard O, Bénet T, Gaymard A, Campoy S, Bothelo-Nevers E, et al.
Cluster of coronavirus disease 2019 (Covid-19) in the French Alps, 2020. Clin
Infect Dis. (2020) 71:825–32. doi: 10.1093/cid/ciaa424
23. Huang BR, Lin YL, Wan CK, Wu JT, Hsu CY, Chiu MH, et al. Co-
infection of influenza B virus and SARS-CoV-2: a case report from
Taiwan. J Microbiol Immunol Infect. (2021) 54:336–8. doi: 10.1016/j.jmii.2020.
06.011
8 June 2021 | Volume 8 | Article 681469
Dadashi et al.
24. Kakuya F, Okubo H, Fujiyasu H, Wakabayashi I, Syouji M, Kinebuchi T. The
first pediatric patients with coronavirus disease 2019 (COVID-19) in Japan;
the risk of co-infection with other respiratory viruses. Japan J Infect Dis.
(2020):JJID−2020. doi: 10.7883/yoken.JJID.2020.181
25. Khodamoradi Z, Moghadami M, Lotfi M. Co-infection of coronavirus disease
2019 and Influenza A: a report from Iran. Arch Iran Med. (2020) 23:239–
43. doi: 10.34172/aim.2020.04
26. Konala VM, Adapa S, Naramala S, Chenna A, Lamichhane S, Garlapati
PR, et al. A case series of patients coinfected with Influenza and
COVID-19. J Invest Med High Impact Case Rep. (2020) 8:1–7.
doi: 10.1177/2324709620934674
27. Konala VM, Adapa S, Gayam V, Naramala S, Daggubati SR, Kammari CB,
et al. Co-infection with influenza A and COVID-19. Eur J Case Rep Int Med.
(2020) 7:001656. doi: 10.12890/2020_001656
28. Li D, Wang D, Dong J, Wang N, Huang H, Xu H, et al. False-negative
results of real-time reverse-transcriptase polymerase chain reaction for
severe acute respiratory syndrome coronavirus 2: role of deep-learning-
based CT diagnosis and insights from two cases. Korean J Radiol. (2020)
21:505. doi: 10.3348/kjr.2020.0146
29. Miatech JL, Tarte NN, Katragadda S, Polman J, Robichaux SB. A
case series of coinfection with SARS-CoV-2 and influenza virus in
Louisiana. Res Med Case Rep. (2020) 31:101214. doi: 10.1016/j.rmcr.2020.
101214
30. Sang CJ, Heindl B, Von Mering G, Brott B, Kopf RS, Benson
PV, et al. Stress-Induced cardiomyopathy precipitated by
COVID-19 and Influenza a coinfection. JACC Case Rep. (2020)
2:1356–8. doi: 10.1016/j.jaccas.2020.05.068
31. Singh B, Kaur P, Reid RJ, Shamoon F, Bikkina M. COVID-19 and
Influenza Co-infection: report of three cases. Cureus. (2020) 12:e9852.
doi: 10.7759/cureus.9852
32. Wu X, Cai Y, Huang X, Yu X, Zhao L, Wang F, et al. Co-infection with SARS-
CoV-2 and influenza a virus in patient with pneumonia, China. Emerg Infect
Dis. (2020) 26:1324–6. doi: 10.3201/eid2606.200299
33. Zou B, Ma D, Li Y, Qiu L, Chen Y, Hao Y, et al. Are they just
two children COVID-19 cases confused with flu? Front Pediatr. (2020)
8:341. doi: 10.3389/fped.2020.00341
34. Jiang S, Liu P, Xiong G, Yang Z, Wang M, Li Y, et al. Co-
infection of SARS-CoV-2 and multiple respiratory pathogens in
Frontiers in Medicine | www.frontiersin.org
COVID-19 and Influenza Co-Infection
children. Clin Chem Lab Med. (2020) 58:1160–1. doi: 10.1515/cclm-
2020-0434
35. Lansbury L, Lim B, Baskaran V, Lim WS. Co-infections in people with
COVID-19: a systematic review and meta-analysis. J Inf. (2020) 81:266–
75. doi: 10.1016/j.jinf.2020.05.046
36. van Riel D, Munster VJ, de Wit E, Rimmelzwaan GF, Fouchier RA, Osterhaus
AD, et al. Human and avian influenza viruses target different cells in the
lower respiratory tract of humans and other mammals. Am J Pathol. (2007)
171:1215–23. doi: 10.2353/ajpath.2007.070248
37. John ALS, Rathore AP. Early insights into immune responses during COVID-
19. J Immunol. (2020) 205:555–64. doi: 10.4049/jimmunol.2000526
38. Bai L, Zhao Y, Dong J, Liang S, Guo M, Liu X, et al. Co-infection with
influenza A virus enhances SARS-CoV-2 infectivity. Cell Res. (2021) 31:395–
403. doi: 10.1038/s41422-021-00473-1
39. Yue H, Zhang M, Xing L, Wang K, Rao X, Liu H, et al. The epidemiology
and clinical characteristics of co-infection of SARS-CoV-2 and influenza
viruses in patients during COVID-19 outbreak. J Med Virol. (2020) 92:2870–
3. doi: 10.1002/jmv.26163
40. Fanelli D, Piazza F. Analysis and forecast of COVID-19
spreading in China, Italy and France. Chaos Solit Fract. (2020)
134:109761. doi: 10.1016/j.chaos.2020.109761
41. Khalil I, Barma P. Sub-continental atmosphere and inherent immune system
may have impact on novel Corona Virus’ 2019 (nCovid-19) prevalence in
South East Asia. Mymen Med J. (2020) 29:473–80.
42. Cox NJ, Subbarao K. Global epidemiology of influenza: past and present. Ann
Rev Med. (2000) 51:407–21. doi: 10.1146/annurev.med.51.1.407
Conflict of Interest: The authors declare that the research was conducted in the
absence of any commercial or financial relationships that could be construed as a
potential conflict of interest.
Copyright © 2021 Dadashi, Khaleghnejad, Abedi Elkhichi, Goudarzi, Goudarzi,
Taghavi, Vaezjalali and Hajikhani. This is an open-access article distributed
under the terms of the Creative Commons Attribution License (CC BY). The use,
distribution or reproduction in other forums is permitted, provided the original
author(s) and the copyright owner(s) are credited and that the original publication
in this journal is cited, in accordance with accepted academic practice. No use,
distribution or reproduction is permitted which does not comply with these terms.
9 June 2021 | Volume 8 | Article 681469